PROJECT SUMMARY Type 2 diabetes affects 1 in every 11 adults in the United States, and is a leading cause of death. High quality dietary intake is independently and strongly associated with lower risk of type 2 diabetes. The metabolic processes connecting dietary intake and diabetes, however, remain unclear. Understanding these biological processes between dietary intake and diabetes can help to establish new and effective individualized targets for treatment and prevention. The expression of compounds related to metabolism and cellular processes is called metabolomics. The objective of this proposal is to determine the identity of metabolites associated with a low-diabetes-risk dietary pattern, to investigate the association of these metabolites with incident diabetes, and the causal pathways related to the action of these metabolites, and to examine changes in the levels of these metabolites in a pilot dietary intervention with a low-diabetes-risk food. Aim 1 will use data and biospecimens from the Multi-Ethnic Study of Atherosclerosis (MESA), the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study and the Rotterdam Study (RS) to determine the association of a low-diabetes-risk dietary pattern with known and novel metabolites. We will validate newly discovered metabolites within the Airwave cohort. Aim 2 associates these newly identified metabolites with incident diabetes and examines the extent to which they mediate the relationship between diet and diabetes. It also places the metabolites within a biological context using network analysis techniques. Aim 3 uses data and biospecimens from an existing pilot trial of a short-term walnut supplement in individuals with prediabetes to evaluate changes in metabolites with the intervention. The candidate for this Mentored Patient-Oriented Research Career Development Award, Dr. Meghana Gadgil, is a General Internist and an Assistant Professor in the Division of General Internal Medicine at the University of California, San Francisco. Dr. Gadgil is a physician-investigator with a strong background in nutrition and diabetes. In this proposal, she will examine novel associations between dietary intake, metabolite expression and type 2 diabetes incidence. This work will serve as the foundation for her overarching career goal: to become an independent clinical investigator focused on prevention of diabetes in high-risk populations through the use of dietary interventions. Dr. Gadgil will commit to structured didactic training and mentored research experience in the areas of 1) techniques for metabolomic analysis and interpretation; 2) training in network and pathway analysis; 3) clinical trial design and management; and 4) career development skills. This study is relevant and timely, as the incidence of both diabetes and its risk factors continues to rise, and personalized dietary strategies for prevention are few. The proposed investigations will contribute understanding, new knowledge, and potential targets of dietary intervention for diabetes prevention.